As more and more polypeptides become of medicinal importance there is increasing incentive to improve the methods by which they may be synthesized. In recent years, peptides which have been found to be of possible pharmacological importance include those active against various cancers, diabetes, plant toxins, etc. Others have shown specific activity as growth promoters or suppressants, antibiotics, insecticides, contraceptives, antihypertensives, sleep-inducers, anti-depressants, analgesics, etc. The list is long and varied. In many cases those most interested in obtaining such materials for research, commercial or other purposes are not necessarily those with extensive experience in the art of peptide synthesis. New simplified methods of obtaining pure peptides of defined structure are clearly needed.
Currently syntheses of polypeptides in solution by classic or various repetitive methods or on a solid support (Merrifield) are popular techniques. Solution methods have the advantage of being easily monitored and allowing purification of intermediates, if necessary at any stage. A major drawback is the relative slow pace of the synthesis with each step being carried out manually.
The major advantage of the Merrifield method is its easy automation so that unattended, computer-controlled machine synthesis is possible. Unfortunately, the method suffers from an inherent deficiency due to the insoluble nature of the support on which the synthesis proceeds. Unless each acylation step occurs with 100% efficiency (an impossible goal for higher peptides), mixtures will inevitably be built up on the polymer. The longer the chain, the greater will be the contamination by undesired side reactions. Products produced in all such reactions remain to contaminate the desired product when at the end of the cycle it is removed from the polymeric matrix. The properties of these peptides will not differ sufficiently for peptides of greater than about 20-30 residues to make efficient separation feasible. The isolation of peptides of defined structure is therefore difficult for lower peptides and essentially impossible for higher peptides or proteins.